cells Review COVID-19, Renin-Angiotensin System and Endothelial Dysfunction Razie Amraei * and Nader Rahimi * Department of Pathology, School of Medicine, Boston University Medical Campus, Boston, MA 02118, USA * Correspondence: [email protected] (R.A.); [email protected] (N.R.); Tel.: +1-617-638-5011 (N.R.); Fax: +1-617-414-7914 (N.R.) Received: 3 June 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1–9 and Ang 1–7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19. Keywords: SARS-CoV-2; endothelial dysfunction; ACE2; endothelial cell injury; CD209L; L-SIGN 1. Introduction The severe acute respiratory syndrome (SARS) epidemic, which was caused by SARS-CoV, emerged in 2002–2003 in southern China and soon spread to Europe and North America [1–3]. A novel coronavirus, SARS-CoV-2, was originally found in patients with severe pneumonia in Wuhan, China at the end of 2019 [4,5]. The disease caused by SARS-CoV-2 was named as COVID-19 [6,7]. SARS-CoV-2 was able to spread rapidly and efficiently, which may account for its significant lethality compared to related viruses such as SARS-CoV and MERS-CoV. Since December 2019, COVID-19 has spread around the world, causing a pandemic that threatens global public health with high mortality in humans and resulted in near complete halt in economic and social activities around world. As of today (8 July 2020), SARS-CoV-2 has infected more than 11 million people and killed over 544,000 worldwide (data compiled by Johns Hopkins University). The major leading cause of mortality in patients with COVID-19 is respiratory failure from acute respiratory distress syndrome (ARDS) [1]. Other causes of mortality include multiorgan failure involving heart and the kidneys [8,9]. However, individuals Cells 2020, 9, 1652; doi:10.3390/cells9071652 www.mdpi.com/journal/cells Cells 2020, 9, 1652 2 of 18 with comorbidities such as hypertension, diabetes, and obesity have worst outcomes and, in general, men are more affected than women [10]. Endothelial dysfunction is an important component of a number of human diseases that also represents the common denominator of all COVID-19 co-existing conditions such as hypertension, diabetes, and obesity which are major contributing factors for COVID-19-related deaths. Consistent with this hypothesis, other clinical manifestations of COVID-19 include cardiac injury [9] and Cells 2020, 9, x 2 of 19 hypercoagulability as measured by an increased in D dimer and Von Willebrand factor (VWF) levels [11–14].However, A recent individuals study foundwith comorbidities that nearly such as 72% hypertension, of non-survivors diabetes, and obesity of COVID-19 have worst had evidence outcomes and, in general, men are more affected than women [10]. of hypercoagulabilityEndothelial [15]. dysfunction In addition, is an inflammatoryimportant componen markerst of a number including, of human diseases C-reactive that also protein, ferritin, interleukin (IL)-6,represents IP-10, the common MCP1, denominator MIP1A, of and all COVID-19 TNF-α co-existingall were conditions elevated suchin as hypertension, COVID-19 patients [16]. diabetes, and obesity which are major contributing factors for COVID-19-related deaths. Consistent Numerous factorswith this such hypothesis, as inflammation other clinical manifestations could contribute of COVID-19 to theinclude hypercoagulability cardiac injury [9] and in COVID-19 patients. However,hypercoagulability pulmonary as measured and by peripheral an increased in endothelial D dimer and Von cell Willebrand injury factor due (VWF) to directlevels SARS-CoV-2 infection is a likely[11–14]. scenario, A recent asstudy endothelial found that nearly cell injury72% of non-survivors can strongly of activateCOVID-19 thehad evidence coagulation of system [17] hypercoagulability [15]. In addition, inflammatory markers including, C-reactive protein, ferritin, and aggressiveinterleukin immune (IL)-6, response IP-10, MCP1, could MIP1A, further and TNF- augmentα all were endothelial elevated in COVID-19 dysfunction. patients [16]. Considering that Von WillebrandNumerous factor (VWF) factors such levels as inflammation is significantly could contribute elevated to inthe COVID-19 hypercoagulability patients in COVID-19 (529 U /dL compared patients. However, pulmonary and peripheral endothelial cell injury due to direct SARS-CoV-2 to 100 U/dL, normal)infection further is a likely supportsscenario, as endothelial the hypothesis cell injury of can SARS-CoV-2 strongly activate induced the coagulation endothelial system dysfunction or damage [13].[17] VWF and aggressive is a circulating immune response adhesive could further glycoprotein augment endothelial that is dysfunction. secreted byConsidering endothelial cells and that Von Willebrand factor (VWF) levels is significantly elevated in COVID-19 patients (529 U/dL platelets and itscompared levels isto 100 elevated U/dL, normal) in vasculitis, further supports inflammation, the hypothesis of aging SARS-CoV [18-2], induced and diabetes endothelial [ 19], conditions that are all associateddysfunction withor damage endothelial [13]. VWF dysfunction.is a circulating adhesive VWF glycoprotein activates that platelets is secreted leading by to platelet aggregation [20endothelial], acts as cells a carrier and platelets of coagulation and its levels is factorelevated VIII,in vasculitis, and contributesinflammation, aging to blood [18], and coagulation [21]. diabetes [19], conditions that are all associated with endothelial dysfunction. VWF activates platelets Moreover, VWFleading is a to key platelet player aggregation in vasculature [20], acts as a carrier system of coagulatio including,n factor regulationVIII, and contributes of angiogenesis to and vascular permeability.blood coagulation The chest [21]. Moreover, X-ray or VWF computed is a key player tomography in vasculature system (CT) scanincluding, found regulation extensive vascular of angiogenesis and vascular permeability. The chest X-ray or computed tomography (CT) scan damage as wellfound as evidence extensive vascular of respiratory damage as well distress as eviden ince of COVID-19 respiratory distress patients in COVID-19 leading patients to conclusion that COVID-19 couldleading bea to disease conclusion that that primarily COVID-19 could damages be a disease the vascularthat primarily endothelium damages the vascular [22]. The interaction endothelium [22]. The interaction between comorbidity factors, SARS-CoV-2, and vascular between comorbiditydysfunction/injury factors, is SARS-CoV-2,shown (Figure 1). and vascular dysfunction/injury is shown (Figure1). Figure 1. Role of comorbidity factors and SARS-CoV-2 in vascular dysfunction and vascular injury. Endothelial dysfunction is associated with aging and conditions such as hypertension and diabetes. SARS-CoV-2 can induce vascular damage directly or indirectly by stimulating immune response which results in excessive cytokine production (cytokine storm) which also can lead to vascular damage. SARS-CoV-2 induced vascular damage alone or in combination with pre-existing endothelial dysfunction can lead to multisystem organ failure and death. Key biochemical factors and cellular responses involved in the SARS-CoV-2 induced endothelial damage and endothelial dysfunction are shown. Cells 2020, 9, 1652 3 of 18 2. Novel Severe Acute Respiratory Syndrome Coronavirus-19 The name of coronavirus is derived from the Latin word “corona” meaning crown. It is named as such because of the large spike protein (S protein) molecules on the virions surface that creates a crown-like shape. In general, coronaviruses are classified into at least four major genera, α, β, δ, and γ [23,24]. SARS-CoV and SARS-CoV-2 belong to the β-genus [25,26] and are considered zoonotic pathogens [27] that can infect various species, particularly